Extended consanguineous kindreds with hereditary hearing impairment are ideally suited to the identification of genes critical to hearing. Since 1997, geneticists from Seattle, Tel Aviv, and Bethlehem have worked with Israeli and Palestinian medical geneticists and otolaryngologists to identify genes for hereditary hearing impairment in Middle Eastern families. Thus far, we have cloned POU4F3 as DFNA15 and myosin IlIA as DFNB30. In seven other kindreds with hereditary hearing impairment, gene mapping is underway. These kindreds are sufficiently informative that the critical gene can be cloned from a single family if all genes map to different locales. Our triangular collaboration proposes: 1. To continue to evaluate and enroll kindreds from the Middle East with inherited hearing loss. 2. To map then identify the gene(s) responsible for hereditary hearing impairment in each kindred. 3. For each newly identified gene, to determine penetrance and variable expressivity of the phenotype among relatives of all genotypes. 4. To evaluate patterns of expression of newly identified genes in the mouse ear by developmental stage, using in situ hybridization and immunohistochemistry. 5. To identify any mouse model with a mutation in the same gene and evaluate the phenotype. The strengths of this project are: the extended families with hereditary hearing impairment already participating in the project; the expertise of the collaborating otolaryngologists in identifying critical features of hearing loss; the experience of the UW laboratory with mapping and positional cloning of human genes; the experience of the Tel Aviv group in characterizing models of hereditary hearing impairment; and the demonstrated success of the collaboration in integrating our efforts to find and characterize genes critical to development and maintenance of hearing.